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RESEARCH COMMUNICATION |
a Friedrich Miescher Institute, Basel CH-4058, Switzerland
b Department of Medicine, University of California at San Francisco, California 94143, USA
c Department of Clinical Research, University of Bern, CH-3004, Bern, Switzerland
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: Ets family • ESX promoter • ESX expression and mammary gland differentiation
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Although its expression profile suggests that ESX is associated with the development of both simple and stratified epithelium (10), detailed studies have been performed only in the latter and have shown that ESX is unique among transcription factors generally, and Ets factors specifically, for its restricted expression in the most terminally differentiated of epidermal cells (6, 8). A limited in situ analysis of normal human mammary tissue demonstrated low but heterogeneous levels of ESX transcript expression restricted to the polarized simple epithelium of ductules and terminal ductal-lobular units (5). To evaluate ESX expression during all differentiation stages of mammary epithelium, mouse ESX cDNA and genomic sequences were cloned and compared to their human counterparts, then used to study postnatal rodent models of mammary gland development. The inductive influences controlling ESX expression were explored by transient transfection of an ESX promoter-reporter construct into a breast cancer cell line (SKBr3) responsive to heregulin-ß (HRG) and epidermal growth factor (EGF). RNA samples probed for ESX expression were derived from different stages of cultured HC11 mouse mammary epithelial cells, first made competent for lactogenesis and then hormonally induced to synthesize ß-casein (11, 12). These results were compared to ESX Northern blots of virgin, pregnant, lactating, and involuting mouse mammary glands. Last, mouse and rat mammary glands collected during involution were also compared to the involuting ventral prostate gland of rats to demonstrate that maximal induction of ESX occurs during this stage of glandular regression, suggesting an association with epithelial apoptosis.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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FIXII 129SV mouse genomic library (Stratagene, San Diego, Calif.) was screened using a 5' cDNA probe from hESX (5; Genbank accession number U66894) to isolate a clone from which a 7.75 kb BamHI fragment was subcloned into pBluescript SK (Stratagene). Upon full sequencing, this genomic clone was found to contain 3.6 kb of sequence upstream from the ATG-start codon (beginning exon 2), about 2.9 kb upstream of the transcriptional start site. The deduced organization of 9 exons (8 coding) and 8 introns spanning 4.9 kb of genomic sequence was subsequently found to be similar to that reported by Tymms et al. (7). This mESX genomic sequence was compared to a previously isolated and fully sequenced 1.8 kb BglII-BglII human genomic clone containing 1.5 kb of hESX promoter sequence upstream of exon 1 and the 5' half of intron 1. A 1.1 kb Bluescript subclone encoding the entire mESX cDNA was derived from 129SV mouse ES cell total RNA by reverse transcriptase-polymerase chain reaction using specific primers extending 5' and 3' from the respective ATG-start and TAA-stop codons in the genomic sequence, and the entire cDNA subclone was sequenced. All sequencing was performed on an ABI Prism Automated DNA Sequencer (model 377) using 3'-dye labeled ddNTP terminators. Computer alignments of genomic and cDNA mESX and hESX sequences were performed, and a comparison of genomic and cDNA mESX sequences was used to determine exon and intron boundaries. Conserved murine and human promoter elements as well as putative amino acid domain homologies were identified from PIR protein, SWISS-PROT, and PROSITE databases by GCG computer search (Genetics Computer Group, Wisconsin Package 3.0, Madison, Wis.).
Growth factors and tissue culture conditions
Recombinant human EGF was commercially obtained (Sigma, St. Louis, Mo.). Recombinant human HRG isoforms were kindly provided (Amgen; ß1 isoform 177–228) or commercially obtained (NeoMarkers; full-length ß1 isoform), with no significant difference in activity detected between the truncated and full-length ß1 isoforms. SKBr3, MCF-7, and MDA-435 breast cancer cell lines (5, 13) and NIH3T3 mouse fibroblasts were all maintained in Dulbecco's modified Eagle's medium (Life Technologies, Inc., Paisley, U.K.) supplemented with 10% fetal calf serum. HC11 cells, derived from midpregnant BALB/c mouse mammary gland tissue, were maintained in culture using a growth medium consisting of RPMI-1640, 10% heat-inactivated fetal calf serum, 5 µg/ml bovine insulin, and either 2 nM HRG or 2 nM EGF (11, 12). HC11 cells were induced into lactogenic competency by culturing them in growth media and maintaining them at confluence for 3 days (12). These competent cultures were then induced to terminally differentiate and produce ß-casein by incubation for 1–6 days in DIP induction medium (RPMI-1640, 5 µg/ml ovine prolactin, 5 µg/ml insulin, and 1 µM dexamethasone).
Northern blot analysis of cell and tissue RNA samples
RNA samples included commercial blots of polyA-RNA from 7- to 17-day-old mouse embryos (Clontech, Palo Alto, Calif.) and total RNA extracted from HC11 cell cultures, excised mouse (BALB/c) and rat (Sprague Dawley) inguinal mammary glands (virgin, pregnant, lactating, and involuting), and excised rat ventral prostate glands (pre- or postcastration). Extractions of total RNA were performed on snap-frozen (liquid nitrogen) cell pellets or excised glands (14), using either the guanidinium isothiocyanate or Trizol (Gibco BRL, Paisley, U.K.) method. When indicated, polyA-enriched RNA from mammary or prostate tissue was prepared using oligo dT-cellulose (Boehringer-Mannheim, Mannheim, Germany). Either 10 µg of total RNA or 5 µg poly(A)-enriched RNA/sample was electrophoresed into 1% agarose gels and transferred onto either nylon (Zeta-probe, BioRad, Richmond, Calif.) or nitrocellulose filters, which were then UV cross-linked using a Stratalinker 1800 (Stratagene). After ethidium bromide or acridine orange staining to quantitate transfer of 18S and 28S RNA, filters were hybridized with a randomly primed and [32
P]dATP-labeled 300 bp cDNA fragment from the amino-terminal mESX coding region and given final washes at 65°C in 0.2x SSC prior to autoradiography.
ESX promoter activation in transient transfection assay
Luciferase (luc) reporter constructs (in pGL2-Basic Vector; Promega, Madison, Wis.) containing either 0.4 kb (-349 bp to +61 bp) of mESX proximal promoter having >80% homology to hESX (mESX-luc) or 1.1 kb (-349 bp to +704 bp) of proximal promoter with an additional 5' untranslated sequence up to the ATG initiation codon (mESXL-luc) were constructed by polymerase chain reaction amplification from the murine genomic clone. Transient transfection of mESX-luc reporter (1 µg DNA) in 6 µl of lipofectamine (Gibco BRL) in serum-free medium (SFM) was performed in replicate tissue culture wells containing 60% confluent (~1x105) cells. After 5 h, the lipofectamine-containing media was replaced with SFM; 12 h later, cell cultures were induced with 10% serum-containing media ± growth factor (HRG or EGF) at the concentrations indicated. The transiently transfected cell cultures were then harvested at 0– 24 h after serum ± growth factor induction, extracts were prepared, and luciferase activity was measured as recommended by the vendor (Promega).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Fig. 1.
This comparison of the primary structures reveals 87% amino acid identity and maps the 7 exon boundaries within the encoded 371 amino acids of ESX.
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Comparing the 2.9 kb of mESX promoter-containing sequence with that of a formerly cloned 1.5 kb hESX promoter-containing genomic fragment (5), and aligning both with reference to exon 1 and a previously determined hESX 5' untranslated region (UTR) sequence (6), showed 
50% bp homology between the most upstream genomic sequences (-1500 bp to -350 bp). In contrast, the proximal ESX promoter regions (-350 bp to +50 bp) showed 83% homology at the nucleotide level between mouse and human genes, which is demonstrated in Fig. 2.
The notable features in this proximal promoter region include conservation of six different consensus response elements (Ets, AP-2, SP1/GC box, USF, Oct, NF-
B), a CCAAT box at -75 bp, and a putative pyrimidine-rich initiator element (Inr) capable of specifying transcript initiation from the TATA-less murine promoter.
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To verify that this homologous region of the proximal promoter can confer growth factor-induced transcriptional up-regulation of mESX, as is known to occur in hESX-overexpressing breast cancer cells (5), the activities of two different mESX promoter-reporter constructs (0.4 kb mESX-luc and 1.1 kb mESXL-luc) were assessed by transient transfection into cultured cells expressing negligible (NIH3T3), low (MCF-7, MDA-435), or high (SKBr3) levels of endogenous ESX (5). Since no significant differences in promoter activity were observed between the 1.1 kb mESXL-luc and the 0.4 kb mESX-luc constructs, the smaller mESX-luc construct was used for all consequent experiments. The negligible and low ESX-expressing cell lines consistently showed minimal reporter activity unresponsive to culture stimulation by serum ± growth factors (NIH3T3, MDA-453) or estradiol (MCF-7). In contrast, mouse NIH3T3 cells engineered to overexpress human ErbB receptor pairs (ErbB2+ErbB1=NE2/1 cells; ErbB2+ErbB3=NE2/3 cells; ErbB2+ErbB4=NE3/4 cells) and with intracellular signaling upon appropriate ErbB ligand stimulation (unpublished results) showed ligand-inducible increases in mESX promoter activity in the presence of serum. NE2/1 cells produced mESX-luc reporter up-regulation in response to EGF, whereas NE2/3 and NE2/4 cells responded similarly to HRG (data not shown), demonstrating the functionality of this ectopic mESX promoter within mouse cells activated by human ErbB receptors.
SKBr3 cells, which overexpress ErbB2 and also moderately express ErbB1 and ErbB3 receptors, were used to study mESX promoter induction since they were known to produce an immediate increase in endogenous ESX transcripts after culture exposure to HRG (5). As shown in Fig. 3,
treatment of SKBr3 for various intervals (0–24 h) produced serum and growth factor (HRG, EGF)-inducible increases in mESX-luc reporter activity. Serum supplementation alone produced a three- to fourfold maximal induction of promoter activity, which peaked within 8 h of treatment and then declined to near serum-free basal promoter activity by 24 h ( Fig. 3A). When these SKBr3 cells were treated with 1 nM HRG in addition to serum supplementation, a sevenfold peak induction over basal promoter activity was observed at 8 h and promoter activity was still elevated nearly fourfold over basal levels 24 h after treatment ( Fig. 3A). HRG concentrations from 0.1 to 2 nM produced comparable enhancements in mESX promoter activity after 8 h (data not shown), ranging from two- to threefold over the peak activity produced by serum alone ( Fig. 3). At this same time point, EGF concentrations of up to 4 nM (in serum-supplemented media) also enhanced mESX promoter activity to a similar (although slightly lesser) degree as HRG ( Fig. 3B). In the absence of serum, neither HRG nor EGF produced any significant mESX promoter induction. Insulin (5 µg/ml±serum-supplementation) had no significant effect on mESX promoter activity in SKBr3 cells ( Fig. 3B).
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Epithelial-specific ESX mRNA expression has been shown for various mouse tissues after fetal day 17, but not during earlier embryonic development or adult mouse mammary gland differentiation (7). As shown in the Fig. 4
Northern blot, mouse embryos exhibit progressive induction of a 2.2 kb ESX transcript after fetal day 7, with 17-day transcript levels about 10-fold higher than those of 11-day-old embryos, which is consistent with the earliest onset of epithelial differentiation and progressive fetal growth of epithelial organs and tissues. Before day 17, embryos show no detectable evidence of the alternatively spliced larger ESX transcript (3.8–4.1 kb) noted in later stage fetal and adult organs and malignant tissues (5–8).
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Postembryonic mammary gland expression of ESX was evaluated in three separate experiments where RNA was isolated from mouse glands taken at various stages of differentiation including that of virgin, pregnant, lactating, and involuting mammary glands. In general, a basal level of ESX expression was seen in virgin and first-pregnancy glands, which declined to undetectable levels after 2–3 days of lactation and increased to maximal levels after weaning and involution. Figure 5
shows a representative stage-specific Northern blot profile of ESX expression. RNA samples from 8- to 12-day involuting glands revealed persistently high ESX expression. These later time points are beyond the active phases of mammary gland involution and after most of the molecular and histologic correlates of apoptosis and tissue remodeling have already peaked (14–16). A fully regressed mouse mammary gland resected 8 wk after weaning also showed maximal ESX expression comparable to peak transcript levels observed within the first 12 days of involution ( Fig. 5; lane R vs. involuting day 10 lane).
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A panel of rat mammary gland RNA samples was also probed and confirmed this stage-specific profile of ESX expression ( Fig. 6).
Rat mammary ESX expression was basal during pregnancy, undetectable during lactation, and showed reinduction to maximal levels within 3 days of weaning and involution. Given that normal prostate expresses ESX (5) and regressing prostatic tissue shows morphological and biochemical features similar to involuting mammary tissue (14), we looked for changes in ESX expression during castration-induced involution of the adult rat ventral prostate. As with the rodent mammary tissue, rat prostate expression of ESX appears highest during glandular involution ( Fig. 6).
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Detailed studies in stratified epithelium have shown that ESX expression is restricted to the most terminally differentiated epidermal keratinocytes (6, 8). Since ESX transcripts decline to undetectable levels during lactation, when the mammary gland is composed of fully differentiated secretory epithelium, we tried to simulate this in vivo observation using cultured HC11 cells, which can be induced into lactogenic competency on exposure to growth factors and then hormonally stimulated to differentiate and produce the milk protein, ß-casein (11, 12). Proliferating HC11 cells express basal levels of ESX ( Fig. 7;
lane G) until they reach confluence and a state of lactogenic competence (2–3 days after culture confluence), when ESX expression increases dramatically ( Fig. 7; lanes C vs. C2 and C3). Upon growth factor (HRG or EGF) withdrawal and administration of lactogenic hormones (DIP induction medium), these competent and terminally differentiating cells express increasing amounts of ß-casein while ESX transcript levels fall concurrently to basal levels ( Fig. 7; lanes C3 vs. D1, D3, and D6).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Fig. 1). In addition to the exon 8- and 9-encoded Ets DNA binding domain, these other structural modules include the exon 3-encoded Pointed (A-region) domain, the exon 5- and 6-encoded amphipathic helix and serine-rich box, and the exon 7-encoded bipartite nuclear targeting sequence (5).
Similar patterns of epithelial-specific ESX mRNA expression have been noted in human and mouse tissues (7), suggesting common mechanisms of transcriptional control and promoter regulation in both murine and human genes. Results from this study indicate that mouse and human ESX promoters share a high degree of homology (83% nucleotide identity) over a relatively short region extending ~0.4 kb upstream from the putative transcriptional start site (+1) and just beyond a conserved pair of Ets binding sites adjacent to an AP-2 consensus response element ( Fig. 2). The mESX promoter lacks the TATA box sequence present in hESX (-41 bp). However, both promoters have a typical CCAAT box located ~75 bp upstream of a conserved pyrimidine-rich type Inr, making it likely that both mESX and hESX function as TATA-less promoters. No significant differences in promoter activity were observed between the 1.1 kb mESXL-luc and the 0.4 kb mESX-luc constructs, suggesting that the 0.7 kb of 5' UTR between the Inr and ATG initiation codon (beginning exon 2) does not contain strong promoter regulatory elements.
In addition to conserved Ets and AP-2 response elements, both murine and human ESX proximal promoters share consensus elements for SP1/GC, USF, Oct, and NF-B. Any combination of these response elements could account for the development- and tissue-specific profile of ESX expression common to both mouse and human tissues (7). These same response elements likely contribute to the differential up-regulation of ESX promoter activity observed between high (SKBr3) and low (MCF-7, MDA-435) ESX-expressing cell lines and in SKBr3 and ErbB receptor overexpressing NIH3T3 cells (NE2/1, NE2/3, NE2/4) upon exposure to serum and growth factors (HRG, EGF). HRG, in particular, appears to synergistically enhance ESX proximal promoter activity two- to threefold over the primary threefold stimulatory effect of serum-supplementation alone, consistent with our previous report of HRG-induced up-regulation of ESX mRNA in cultured SKBr3 cells (5). Additional studies are under way to determine the mechanisms and response elements mediating serum, HRG, and EGF induction of ESX promoter activity in these cells. The dramatic changes in ESX mRNA levels observed during normal mammary epithelial differentiation in vitro and in vivo may also be mediated by these same growth factor-responsive promoter elements.
Mammary epithelium requires not only membrane-activated ErbB receptor family members for normal ductal development (17), but also the ErbB receptor ligands EGF and HRG, which are potent in vivo stimulators of mammary epithelial proliferation and differentiation (18–20). The in vivo situation can be simulated in vitro using HC11 cell cultures, in which both HRG and EGF are mitogenic and either one can be used to promote HC11 lactogenic competency, a state of commitment essential for subsequent hormonal induction of terminal differentiation and milk expression (11, 12). The mechanisms associated with lactogenic competency are incompletely understood, but are partially mediated by responses to increased cell–cell interactions and to a reorganized extracellular matrix (21, 22). Our present study demonstrates that in HC11 cells, growth factor-promoted lactogenic competency is associated with a dramatic up-regulation in ESX expression ( Fig. 7).
The changes in ESX expression associated with in vitro induction of HC11 terminal differentiation mimicked some but not all the features of ESX transcript profiles observed during in vivo mammary gland development. Pregnancy represents a developmental stage in which epithelial cell proliferation and increasing commitment to terminal differentiation occur. Unlike the ESX up-regulation observed when proliferating HC11 cells become lactogenically competent, glands from sexually mature virgin and first-pregnancy mice showed no significant variation in their level of ESX expression. However, with in vivo terminal differentiation of mouse and rat mammary epithelium into milk-producing lobuloalveolar units, there was a marked decline in ESX expression ( Figs. 5 and 6) consistent with the fall in ESX transcript levels observed with hormonal induction of ß-casein expression in competent HC11 cells ( Fig. 7). This dramatic decline in ESX expression upon terminal differentiation of mammary epithelial cells in vitro and in vivo is in unique contrast to stratified epithelial systems where ESX expression is up-regulated and restricted to the most terminally differentiated forms of epidermal keratinocytes (6, 8).
ESX may now be added to a small but growing list of epithelial genes known to be repressed during lactogenesis and then dramatically up-regulated with weaning and initiation of mammary gland involution (14–16, 22–24). Increasing ESX transcript levels are evident in the involuting mammary glands of both mouse and rat beginning as early as 1–2 days after weaning. In the rat gland, this induction reaches peak levels within 4 days, whereas in the mouse gland expression is maximal by 8 days and remains high for at least 8 wk, a point when apoptosis and remodeling are completed and the gland is fully regressed. The persistence of high ESX transcript levels in fully regressed mammary glands suggests that the involutional induction of ESX is occurring in newly committed epithelial cells that are destined to survive both apoptotic and remodeling phases of involution. Future in situ analysis will address the possibility that ESX up-regulation occurs in a subpopulation of partially committed and pluripotential ductal epithelium poised to regenerate a fully differentiated milk-producing gland with the next cycle of pregnancy and lactation. Molecular markers that potentially distinguish virgin mammary epithelium from partially or terminally differentiated ductal-lobular elements are of biological and medical interest, as they might ultimately serve to identify women whose breast tissue is more or less vulnerable to malignant transformation (25, 26).
Like the mammary gland, prostatic tissue is subject to involutional changes and its epithelium regresses in a reversible manner after surgical castration or pharmacologically induced androgen ablation. Although the regressing ventral prostate shows morphological and biochemical features of epithelial apoptosis analogous to those of involuting mammary gland, unlike the latter it shows little evidence of tissue remodeling with slight induction of ECM proteinases of the matrix metalloproteinase and serine protease families (14). In contrast, the transition from lactating to involuting mammary gland is well characterized by two distinct phases of apoptosis: an early proteinase-independent phase and a prominent proteinase-dependent later stage (24). In the initial phase (days 1–3 after weaning), the gland's alveoli and supporting mesenchyme remain largely intact, but chromatin cleavage and DNA laddering become detectable along with induction of the same apoptosis-associated genes up-regulated during prostatic involution (14–16, 22–24, 27). During the second stage (days 3–10 after weaning), massive apoptotic cell loss (~50% of the gland's cellularity and 
95% of all alveolar epithelium) results in collapse and dissolution of all milk-producing glands, necessitating a much more extensive protease-mediated ECM remodeling process than that required by the involuting prostate. Despite these differences between involuting breast and prostate glands, ESX transcript levels increased in both in a similar manner ( Fig. 6). Maximal up-regulation of prostatic ESX occurred within 2–4 days of hormonal ablation, concurrent with increases in other apoptosis-associated prostatic transcripts (e.g., sulfated glycoprotein-2, tissue transglutaminase, p53, DDC-4, TGF-ß1, TGF-ßRII) previously demonstrated in these same RNA samples (14) or by other groups (27).
Although a number of ECM proteases are known to be transcriptionally regulated by Ets factors (28, 29), the early and comparable extent of ESX up-regulation observed during involution of prostate and mammary glands and the persistence of up-regulated ESX in fully regressed mammary glands suggest that this Ets family transactivator may be regulating other genes in addition to proteases in cells destined to survive both the apoptotic and remodeling phases of glandular involution. Transglutaminase 3 and TGF-ßRII are two of the few genes identified to date as being transcriptionally up-regulated by ESX (6, 8, 9). The former is closely related to tissue transglutaminase, which, along with TGF-ßRII, is up-regulated in concert with ESX during involution. Thus, our findings should not only stimulate the search for ESX-regulated genes associated with involution and apoptosis, but also provide greater incentive to identify ECM and growth factor-sensitive response elements within the ESX promoter that account for its transcriptional up-regulation during prostate and mammary gland involution.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Abbreviations: EGF, epidermal growth factor; ESX, epithelium-specific Ets transcription factor (epithelial-restricted with serine box); HRG, heregulin; luc, luciferase; SFM, serum-free medium; TGF-ßRII, transforming growth factor ß type II receptor; UTR, untranslated region.
Received for publication April 30, 1998.
Revision received June 1, 1998.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-TGF, and EGF-like growth factors on lobuloalveolar development of the mouse mammary gland in vivo. J. Cell. Physiol. 132, 581–584[Medline]
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